The present invention relates to benzothiazoles and salts thereof, to methods of using such compounds in treating protein tyrosine kinase-associated disorders such as immunologic disorders, and to pharmaceutical compositions containing such compounds.
Protein tyrosine kinases (PTKs) are enzymes which, in conjunction with ATP as a substrate, phosphorylate tyrosine residues in peptides and proteins. These enzymes are key elements in the regulation of cell signaling including cell proliferation and cell differentiation. PTKs comprise, inter alia, receptor tyrosine kinases (RPTKs), including members of the epidermal growth factor kinase family (e.g., HER1 and HER2), platelet derived growth factor (PDGF), and kinases that play a role in angiogenesis (Tie-2 and KDR); and, in addition, non-receptor tyrosine kinases, including members of the Syk, JAK and Src (e.g. src, fyn, lyn, Lck and blk) families (see Bolen, J. B., Rowley, R. B., Spana, C., and Tsygankov, A. Y., xe2x80x9cThe src family of tyrosine protein kinases in hemopoietic signal transductionxe2x80x9d, FASEB J., 6, 3403-3409 (1992); Ulhrich, A. and Schlessinger, J., xe2x80x9cSignal transduction by receptors with tyrosine kinase activityxe2x80x9d, Cell, 61, 203-212 (1990); and Ihle, J. N., xe2x80x9cThe Janus protein tyrosine kinases in hematopoetic cytokine signalingxe2x80x9d, Sem. Immunol., 7, 247-254 (1995)).
Enhanced activity of PTKs has been implicated in a variety of malignant and nonmalignant proliferative diseases. In addition, PTKs play a central role in the regulation of cells of the immune system. PTK inhibitors can thus impact a wide variety of oncologic and immunologic disorders. Such disorders may be ameliorated by selective inhibition of a certain receptor or non-receptor PTK, such as Lck, or due to the homology among PTK classes, by inhibition of more than one PTK by an inhibitor.
A PTK of particular interest is Lck which is found in T cells where it is involved in phosphorylating key protein substrates. It is required for productive antigen receptor signaling and cell activation. In the absence of Lck activity, the T cell receptor (TCR) zeta chain is not phosphorylated, the kinase ZAP-70 is not activated, and Ca2+ mobilization essential for T cell activation does not occur (see Weiss, A. and Littman, D. R., xe2x80x9cSignal transduction by lymphocyte antigen receptorsxe2x80x9d, Cell, 76, 263-274 (1994); Iwashima, M., Irving, B. A., van Oers, N. S. C., Chan, A. C., and Weiss, A., xe2x80x9cSequential interactions of the TCR with two distinct cytoplasmic tyrosine kinasesxe2x80x9d, Science, 263, 1136-1139 (1994); and Chan, A. C., Dalton, M., Johnson, R., Kong, G., Wang, T., Thoma, R., and Kurosaki, T., xe2x80x9cActivation of ZAP-70 kinase activity by phosphorylation of tyrosine 493 is required for lymphocyte antigen receptor functionxe2x80x9d, EMBO J., 14, 2499-2508 (1995)). Inhibitors of Lck are thus useful in the treatment of T-cell mediated disorders such as chronic diseases with an important T cell component, for example rheumatoid arthritis, multiple sclerosis and lupus, as well as acute diseases where T cells are known to play an essential role, for example acute transplant rejection and delayed-type hypersensitivity (DTH) reactions.
The present invention provides benzothiazole compounds of the following formula I and salts thereof, for use as protein tyrosine kinase inhibitors: 
where
p is 0, 1, 2 or 3;
X1 and X2 are each hydrogen, or together form xe2x95x90O or xe2x95x90S;
each R1 is independently selected from:
(1) hydrogen or R6, where R6 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z1, Z2 and one or more (preferably, one or two) groups Z3;
(2) xe2x80x94OH or xe2x80x94OR6;
(3) xe2x80x94SH or xe2x80x94SR6;
(4) xe2x80x94C(O)qH, xe2x80x94C(O)qR6, or xe2x80x94Oxe2x80x94C(O)qR6, where q is 1 or 2;
(5) xe2x80x94SO3H or xe2x80x94S(O)qR6;
(6) halo;
(7) cyano;
(8) nitro;
(9) xe2x80x94Z4xe2x80x94NR7R8;
(10) xe2x80x94Z4xe2x80x94N(R9)xe2x80x94Z5xe2x80x94NR10R11;
(11) xe2x80x94Z4xe2x80x94N(R12)xe2x80x94Z5xe2x80x94R6;
(12) xe2x80x94P(O)(OR6)2;
(13) any two groups R1 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the carbon atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3; or
(14) any two groups R1 may, together with the carbons to which they are attached, form a heterocyclo group, which group is unsubstituted or substituted with Z1, Z2 and Z3;
R2 and R3 are each independently:
(1) hydrogen or R6;
(2) xe2x80x94Z4xe2x80x94R6; or
(3) xe2x80x94Z13xe2x80x94NR7R8;
R4 and R5:
(1) are each independently hydrogen or R6; or
(2) together with the nitrogen atom to which they are attached complete a 3- to 8-membered saturated or unsaturated heterocyclic ring which is unsubstituted or substituted with Z1, Z2 and Z3, which heterocyclic ring may optionally have fused to it a benzene ring itself unsubstituted or substituted with Z1, Z2 and Z3;
R7, R8, R9, R10, R11 and R12:
(1) are each independently hydrogen or R6;
(2) R7 and R8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring with the nitrogen atom to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3; or
(3) any two of R9, R10 and R11 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
R13 is:
(1) cyano;
(2) nitro;
(3) xe2x80x94NH2;
(4) xe2x80x94NHOalkyl;
(5) xe2x80x94OH;
(6) xe2x80x94NHOaryl;
(7) xe2x80x94NHCOOalkyl;
(8) xe2x80x94NHCOOaryl;
(9) xe2x80x94NHSO2alkyl;
(10) xe2x80x94NHSO2aryl;
(11) aryl;
(12) heteroaryl;
(13) xe2x80x94Oalkyl; or
(14) xe2x80x94Oaryl;
R14 is:
(1) xe2x80x94NO2;
(2) xe2x80x94COOalkyl; or
3) xe2x80x94COOaryl;
Z1, Z2 and Z3 are each independently:
(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (16) of the definition of Z1, Z2 and Z3;
(2) xe2x80x94OH or xe2x80x94OZ6;
(3) xe2x80x94SH or xe2x80x94SZ6;
(4) xe2x80x94C(O)qH, xe2x80x94C(O)qZ6, or xe2x80x94Oxe2x80x94C(O)qZ6;
(5) xe2x80x94SO3H or S(O)qZ6;
(6) halo;
(7) cyano;
(8) nitro;
(9) xe2x80x94Z4xe2x80x94NZ7Z8;
(10) xe2x80x94Z4xe2x80x94N(Z9)xe2x80x94Z5xe2x80x94NZ7Z8;
(11) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94Z6;
(12) xe2x80x94Z4xe2x80x94N(Z10)xe2x80x94Z5xe2x80x94H;
(13) oxo;
(14) xe2x80x94Oxe2x80x94C(O)xe2x80x94Z6;
(15) any two of Z1, Z2, and Z3 may together be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; or
(16) any two of Z1, Z2, and Z3 may together be xe2x80x94Oxe2x80x94(CH2)qxe2x80x94Oxe2x80x94;
Z4 and Z5 are each independently:
(1) a single bond;
(2) xe2x80x94Z11xe2x80x94S(O)qxe2x80x94Z12xe2x80x94;
(3) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Z12xe2x80x94;
(4) xe2x80x94Z11xe2x80x94C(S)xe2x80x94Z12xe2x80x94;
(5) xe2x80x94Z11xe2x80x94Oxe2x80x94Z12xe2x80x94;
(6) xe2x80x94Z11xe2x80x94Sxe2x80x94Z12xe2x80x94;
(7) xe2x80x94Z11xe2x80x94Oxe2x80x94C(O)xe2x80x94Z12xe2x80x94; or
(8) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Oxe2x80x94Z12xe2x80x94;
Z7, Z8, Z9 and Z10:
(1) are each independently hydrogen or Z6;
(2) Z7 and Z8, or Z6 and Z10, may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3; or
(3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with Z1, Z2 and Z3;
Z11 and Z12 are each independently:
(1) a single bond;
(2) alkylene;
(3) alkenylene; or
(4) alkynylene;
Z13 is:
(1) a single bond;
(2) xe2x80x94Z11xe2x80x94S(O)qxe2x80x94Z12xe2x80x94;
(3) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Z12xe2x80x94;
(4) xe2x80x94Z11xe2x80x94C(S)xe2x80x94Z12xe2x80x94;
(5) xe2x80x94Z11xe2x80x94Oxe2x80x94Z12xe2x80x94;
(6) xe2x80x94Z11xe2x80x94Sxe2x80x94Z12xe2x80x94;
(7) xe2x80x94Z11xe2x80x94Oxe2x80x94C(O)xe2x80x94Z12xe2x80x94;
(8) xe2x80x94Z11xe2x80x94C(O)xe2x80x94Oxe2x80x94Z12xe2x80x94;
(9) xe2x80x94C(NR13)xe2x80x94;
(10) xe2x80x94C(CHR14)xe2x80x94; or
(11) xe2x80x94C(C(R14)2)xe2x80x94.